Contents1. NIH chief makes call for
cloning research2. Let's get real about gene
therapy: Science stories too often gloss over the
difficulties researchers face3. Immortality in a pill could
100 years someday be considered middle-aged?

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BETHESDA, Md. - The newly installed director of the National Institutes
of
Health publicly stated his views yesterday for the first time on the
cloning
of human tissues, issuing a call for more medical researchers to get
into
the controversial field. His carefully worded statement was made in
reply to
a question about ''therapeutic cloning,'' which President Bush has
said
should be criminalized even when done by privately funded researchers.
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Dr. Elias Zerhouni also hailed work being done on stem cell research
as
''one of the top scientific opportunities of the moment.''
Zerhouni's views on stem cell research and therapeutic cloning could
have
far-reaching impact on the medical research community in Massachusetts
and
elsewhere.
Bush has ordered that stem cell research funded by the government be
limited
to 60 existing lines, and the NIH is prohibited from working on cloning
of
human tissues because of a 1995 law banning certain types of embryonic
research. Zerhouni, who came to the NIH five weeks ago with a vow to
examine
''facts, not factions,'' yesterday said in his first meeting with reporters
since then that he aimed to go where those facts lead on both therapeutic
cloning and stem cell research.
In meeting with a small group of print reporters at the NIH campus
here,
Zerhouni set the tone for his stewardship of the world's largest medical
research facility by saying that he hoped to oversee a ''quantum leap''
in
medical discoveries. That, he said, is the best way to control the
nation's
spiraling health care costs.
''It is very difficult for me to see how the country will overcome
the
difficulties posed by the growth of health care expenditures without
renewed
discovery efforts,'' Zerhouni said. ''The only thing that can really
change
it are quantum leap discoveries that can make a quantum leap difference
in
the delivery of health care.''
That statement led to questions about whether such quantum leaps could
come
without greater stem cell research and human tissue cloning.
Stem cell research and human tissue cloning are opposed by some who
view the
research as involving the destruction of human life.
Asked whether he agrees with Bush's call for legislation that would
criminalize all forms of cloning, which has passed the House but has
stalled
in the Senate, Zerhouni said: ''To me, the science is so early that
what we
need to do is develop the scientific field, get more people into doing
the
research that needs to be done. At this point I don't think we are
anywhere
near clinical implementation. Let's step back for a second.''
A spokesman said later that this was the first time Zerhouni publicly
has
addressed the topic of ''therapeutic cloning,'' which involves the
cloning
of tissues and is different from reproductive cloning of human beings,
which
has no political support.
Zerhouni, who established the Institute for Cell Engineering at Johns
Hopkins University, urged similar restraint in the debate about stem
cell
research. Some scientists believe that such research can eventually
produce
tissue that can be used to cure certain diseases.
''Stem cell research in my mind raises very fundamental questions about
fundamental biological issues,'' Zerhouni said.
''The simple discovery that you may have `plasticity' that changes
the fate
of one cell towards another, or the entire issue of epigenetic programming,
that is for me a revolutionary concept that should rank as one of the
top
scientific opportunities of the moment,'' he said.
Epigenetic programming is a field related to stem cell research in
which
scientists seek to understand why cells have certain functions, and
seek to
change those functions in the laboratory.
As part of that process, scientists hope the reprogrammed cells can
be used
to treat diseases.
The NIH has an enormous impact on the Massachusetts economy, sending
$1
billion annually for research to Boston universities, teaching hospitals,
and biotechnology companies, more than to any other city in the country.
Facilities in the rest of Massachusetts receive $600 million, making
the
state the second-largest recipient of NIH funds after California.
Those amounts have risen steadily as NIH's budget has doubled in the
past
five years, prompting much concern in the research community about
whether
the research dollars now will begin to decline.
Zerhouni said it's ''hard to know'' whether NIH needs another significant
budget increase, and he noted that the Bush administration is operating
under difficult budget constraints.
But Zerhouni's call for a ''quantum leap'' in medical discoveries is
likely
to be interpreted in many quarters as a call for even greater investment
in
research.

This story ran on page A3 of the Boston Globe on 7/3/2002.
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A recent article in the Boston Globe with the intriguing
title, Building a
Better Athlete, seemed to suggest that the ultimate goal of gene therapy
was
to make us all Olympic champions, to help us run faster, jump higher
and
become stronger and slimmer. Like many such stories, it emphasized
the
sensational promise of gene therapy and glossed over the technical
difficulties that researchers in the field are still struggling to
overcome.
The story, like too many similar ones about apparent breakthroughs
in cancer
research or finding the ultimate AIDS vaccine - would have served science
better if it had been more realistic. In fact, gene therapy was first
hailed
as a major milestone in medical research almost two decades ago and
still,
the way ahead is fraught with enormous challenges. It's true that advances
in genetics, including the successful decoding of the human genome,
have
brought the prospect of curing illnesses with healthy genes closer
to
reality. But researchers still have many difficulties to solve before
they
find a way to drive healthy genes into cells to produce proteins. The
first
difficulty lies in the very nature of genes. They are highly unstable
and
disoriented particles that cannot be let loose in the human body. They
have
to be combined with ''vectors'' - special agents that guide them to
the
right cell and protect them from the defence mechanisms of the human
body.
Many agents could act as an escort-cum-bodyguard for the genes. Scientists
have considered viruses, fatty particles, plastics, gels, long-chain
molecules and soapy molecules. Even the famous stem cells are considered
potential candidates for gene vectors. But so far researchers have
been
unable to develop a vector system that can deliver on all fronts. Some
don't
protect the gene adequately, while others shield the genetic material
to the
extent that they are unable to release their cargo once inside the
cell.
Some agents are unable to recognize specific cells while others often
target
healthy cells. Viral vectors are, by far, the most efficient gene vectors,
but viruses raise serious safety concerns. The death of a young patient
during clinical
trials in 1999 led many researchers to divert their attention to synthetic
non-viral vectors. Though less efficient, the hope is that non-viral
vectors
might alleviate some of the safety concerns that plague viral vectors.
Once
the vector has delivered the gene to the cell, we can only sit back
and
watch as a complex biological spectacle unfolds. Once inside the cell,
the
gene supposedly dives into the nucleus and attaches itself to the resident
DNA. Thereafter, the complex mechanism of producing or ''expressing''
the
corresponding protein takes place. Ultimately, it is the protein that
plays
the therapeutic role by suppressing tumours, regenerating new tissue
or
normalizing the functions of vital organs. Much about these mechanisms
is
still shrouded in mystery. How scientists can control or even influence
this
process remains a question mark. If only injecting genes into cells
to
produce proteins were as simple as feeding coins into a vending machine
to
get a soft drink. Cells, unfortunately,
are more intelligent and complex than vending machines.

They generally don't welcome foreign particles, and activate a
number of
defence mechanisms to keep them out.

Cells will even commit suicide rather than submit to invasion.
To outwit
these defences, some scientists have tried to design tiny ''nanoparticle''
vectors that can whisk the gene into the cell surreptitiously. However,
nanoparticles that are too small could fall victim to macrophages -
scavenger cells that hungrily scour the human body, devouring any foreign
particles they find. Probably the best way to overcome the frustrations
of
gene-vector research would be to bring researchers from the life
sciences and materials science to develop hybrids that would combine
the
efficacy and specificity of viral vectors with the safety and versatility
of
synthetic vectors.

Judging from recent literature on the subject, such an approach
has already
taken root and is beginning to bear fruit. The technical difficulties
in
gene-therapy research are compounded by weighty moral and ethical issues.

Altering a person's genetic makeup is, in effect, playing God.
Such
technologies are bound to create a moral backlash in society. They
will
likely recall the horrors of eugenics and raise again the prospect
of
designer babies. Without ethical guidelines, gene therapy could lead
to the
obsolescence of such qualities as talent, effort and perseverance as
physical fitness and intellectual calibre would simply be ''engineered''
by
plugging in the right genetic cocktail. A proper legal and regulatory
framework can prevent such outcomes. Existing laws and guidelines already
deal with human cloning, abortion, animal testing and, more recently,
embryonic stem-cell research. It is imperative to put together similar
legislation to insure
that gene therapy is used to treat only serious conditions and ban
or, at
least, strongly discourage gene therapy for cosmetic enhancement. Finally,
both scientists and science
reporters should adopt a more balanced approach when communicating
to the
public. Articles that exaggerate and mislead only trivialize science,
and
there is really no need to resort to sensationalism. The trials and
tribulations scientists face as they seek new products and
processes make interesting stories in themselves when properly told.
Good
science writing can help the general public better understand and appreciate
the true potential of such promising scientific and medical innovations
as
gene therapy. - Sumitra Rajagopalan is a Montreal-based biomaterials
researcher, science writer and teacher.
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3.The Boston Globe July 2, 2002, Tuesday ,THIRD EDITION
SECTION: HEALTH SCIENCE; Pg. C1 LENGTH: 1613 words
HEADLINE: IMMORTALITY IN A PILL COULD 100 YEARS OLD SOMEDAY BE CONSIDERED
MIDDLE-AGED?BYLINE: By Raja Mishra, Globe Staff
BODY: In the 16th century, Ponce de Leon scoured North America
for the
legendary Fountain of Youth. He discovered Florida instead. But the
Spanish
explorer's quest lives on in the cluttered Cambridge offices of a start-up
company. At Elixir Pharmaceuticals Inc., serious scientists make serious
statements that life-extension pills will be available in the near
future -
drugs that could stretch life to 110 or more disease-free years - granting
middle-age vigor to people now considered elderly. At first blush,
their
tale seems far-fetched. The supporting evidence remains preliminary,
all of
it based on tests in animals. But the field of molecular biology can
already
extend the lifespan of yeast, worms, flies, and mice by tweaking simple
genetic triggers. So, too, the human? "We understand specific proteins
now
that are involved in aging. With these proteins, we can begin to look
for
drugs, for pills," said Dr. Lenny Guarente, the Novartis professor
of
biology at the Massachusetts Institute of Technology and cofounder
of
Elixir. Elixir is not alone. Life extension, once the purview of mystics
and
shamans, alchemists and opportunists, now resides in the portfolio
of a
growing cadre of respected scientists, many in the Boston area, who
predict
testable life extension treatments by the end of the decade. Science
has
long viewed life extension research as slightly nutty and, moreover,
too
messy to provide easy answers; there are just too many ways to age.
But a
revolution in aging genetics over the last decade has produced a new
understanding:
There are indeed many ways to age, but the human genome also probably
contains a few key genes that can be stimulated to prolong life and
health.
Doubters are legion. Many biologists still view the work with caution.
A few
venture capitalists have made initial investments in the science, but
most
await further evidence before plunging into what would be an undeniably
massive potential market. And evolutionary biologists, who view aging
as a
complex organ-by-organ deterioriation, can scarcely conceal their scorn.
"As
adorable as Lenny Guarente may be, he will not come up with an anti-aging
pill. It just won't happen," said University of California at Irvine
biologist Michael Rose, who considers longevity research the product
of
"hubris" and unfounded "technological optimism."

As longevity-increasing genetics progresses, controversy will
probably
grow. "You are going to end up with a huge protest movement of people
opposed to tinkering with life span," said Gary Ruvkun, a genetics
professor
at Harvard Medical School who studies aging. In a sense, 20th-century
medicine was one long, successful life-extension effort. At the start
of the
century, the average American could expect to live into his or her
mid-40s.
Today, life expectancy stands in the mid-70s. A wide array of developments
helped - vaccines, improved sanitation, better surgical techniques,
pharmaceuticals, widespread health education,
to name a few. But, as more humans aged into their 50s and up, the
viruses
and afflictions that were the curse of their youth were replaced by
chronic
and degenerative diseases of old age, such as cancer, heart disease,
diabetes, and Alzheimer's disease. The numerous ways to die seems to
indicate that aging is indeed complex: There are so many potential
killers
that arise for so many reasons.

In 1993, Cynthia Kenyon of the University of California at San
Francisco
published a finding that galvanized the current revolution in aging
genetics. Her team found that a single genetic mutation doubled the
lifespan
of the C. elegans worm. One genetic switch. Until that point,
life-extension studies, beyond recommendations on healthy diet and
exercise,
focused mostly on calorie restriction.

Cutting calorie intake by about 30 percent was long known to lengthen
the
life span of mice, the only proven mammal-longevity strategy. Some
scientists sought to understand why. Even if they found out, however,the
calorie restriction necessary was too severe for widespread human use,
many
scientists concluded. Kenyon's discovery offered a new angle of attack:
Instead of studying the habits of long-lived life forms, why not seek
life-extending genes in
easily studied creatures that reproduce quickly? Guarente soon found
a gene
that, when boosted, increased yeast life span by 50 percent. "If it's
true
for yeast and true for worms, it's likely to be true in humans," said
Harvard Medical School assistant professor David Sinclair, an aging-genetics
specialist, suggesting that these longevity genes were passed from
species
to species as life evolved.

Simple genetic tinkering soon was proved effective in extending
the lives
of flies and mice as well. But will this translate to humans? It is
quite
literally a million-dollar question. In 1997, scientist and venture
capitalist Cindy Bayley met Guarente through a mutual friend. "We realized
we had to form a company. We knew this could be one of those big
breakthroughs," she said, and the two, along with Kenyon, did just
that. By
2000, they had raised $8.5 million from a trio of biotech-focused venture-
capital firms. A name with mystical implications, after
much debate, was selected: Elixir. Currently, they are seeking another
$30
million to further their work. Last month, the firm moved into offices
in
Kendall Square, with limited lab space and shining new office furniture.

Eighteen people work there. Bayley is vice president. In interviews,
Elixir
executives carefully dwell on the science, repeating terms such as
"solid
research" and "testable hypotheses," but recognize that their work
touches
on a primal human yearning - immortality. "There are a lot of interesting
discussions one could have about the implications of this over some
beer and
a nice meal," said Elixir chief executive officer Ed Cannon, who then
quickly steered the conversation back to yeast and worms.

Recent animal research has found at least three or four pathways,
or series
of genes, that are probably involved in age regulation. The pathways,
which
are also present in humans, suggest about a dozen genes as promising
targets
for drugs, Cannon said. The company hopes to test several potential
life-extension drugs on mice within three years, followed shortly by
human
trials. All this work on aging genetics did not render calorie restriction
irrelevant. To the contrary, Guarente found that the gene manipulated
to
make long-living yeast, called SIR2, interacted with a gene that regulates
metabolism, called NAD+, to work its
longevity magic. And NAD+ only showed up in ample quantities when calories
were restricted. Researchers now seek drugs that, in effect, simulate
calorie restriction by
stimulating NAD+, as well as those that boost SIR2 levels.

Guarente and colleagues have theorized that the
calorie-restriction-and-aging link represents a "hunkering-down" strategy:
When times are lean, life forms adapt, extending life in order to ensure
enough time for reproduction. The researchers believe the SIR2-NAD+
combo,
like a fastidious butler, prevents the typical fraying and misfiring
in
other genes that eventually causes cell death and aging. The combination
is
but one of several related genetic pathways related to aging. "I think
it's
a universal mechanism present in yeast and worms and rats - and humans,"
Guarente said. Guarante's company is not alone in the tiny life-extension
marketplace. Last year, a Boston University researcher, Dr. Thomas
Perls,
found in a study
of 90- and 100-year-olds that long life was probably caused by limited
genetic mutations passed through generations. He quickly formed a company,
Centagenetix Inc., to search for
these human genes. Also, a group in Wisconsin with extensive
calorie-restriction experience formed LifeGen Technologies to work
on their
ideas. But how to test the drugs they design? A life-extension clinical
trial could conceivably last a century. Mounting evidence in mice shows
that
those with extended life spans also have dramatically lower rates of
chronic
diseases such as cancer. Officals at the companies said initial tests
of
life-extension pills would
probably focus on single diseases, with data on life span collected
later.
But all this talk of life extension rubs some the wrong way - especially
evolutionary biologists.

"There's no particular mechanism that puts an end to your life
at a
particular age," said evolutionist George C.

Williams, professor emeritus at the State University of
New York at Stony
Brook, who explained that evolution, driven by reproductive competition,
would not preserve genes that regulated life span beyond the child-bearing
years. UC-Irvine's Rose, also a skeptic of the longevity efforts, predicted:
"There will be some limited but interesting breakthroughs. Maybe they'll
give us four more years and the ability to walk around longer."

But University of Connecticut associate professor Dr. Stephen
Helfand, who
discovered a life-extending gene in fruit flies, said, "I don't know
what
will happen. But I don't feel it's necessary to set limits."

Helfand named the gene INDY, for "I'm not dead yet," a quip
from an
absurdist Monty Python film. A certain magical, perhaps absurd,
quality
does hang over the work, Sinclair said. "It is shocking. Instead of
preventing symptoms, you're preventing onset of aging."

A recent interview at his lab was inturrupted by a phone call.
"Another
venture capitalist. They all want me to start a company," he explained
after
hanging up. "You expect me to give up a job at Harvard Medical School?"
Then
he added, half in jest, "Maybe for a million dollars."
Contents
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